We have discovered a new method that resolves proteins on the basis of differences in hydrophobic qualities. This permits the separation of proteins of very similar charge and size, such as histones. There is considerable evidence that histones inhibit gene transcription in eukaryotes. Our method has revealed a degree of multiplicity and tissue-specificity previously undetected for this family of chromosomal proteins. Our objective is to investigate the nature and function of tissue- specific histones. New histone species, isolated by our procedure, will be characterized with respect to amino acid composition, end groups, molecular weight and affinity for nonionic detergents. The development of tissue-specific histone patterns in the course of cell differentiation will be studied by comparing mouse blood cells at different stages of maturation. Changes in the histone complement during carcinogenesis will be investigated by comparing chemically induced rat liver tumors and mouse leukemic cells with corresponding normal cells of comparable degree of differential and proliferation. An attempt will be made to isolate newly synthesized tissue- specific histones from the cytosol and nuclear sap by immunological techniques.